DESCRIPTION (from the application): Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata. There is evidence that huperzine A may compare favorably in symptomatic efficacy to cholinesterase inhibitors currently in use and under development. In addition, huperzine A has antioxidant and neuroprotective properties that suggest that it may be useful as a disease-modifying agent in AD. The drug is currently available as a nutriceutical in this country and is being used by some U.S. clinicians to treat AD. However, there have been no controlled clinical trials outside of China assessing its toxicity and efficacy. We propose to initiate the evaluation of huperzine A in the treatment of AD with a short-term randomized controlled trial of its effect on cognitive function. A total of 80 subjects will be randomly assigned to two equal groups: group A will receive huperzine A 100 ug bid-for-4-weeks, followed by 200 ug bid for 4 weeks, 300 ug bid for 4 weeks and 400 ug bid for 4 weeks; group B will receive placebo for 8 weeks, followed by huperzine A 100 ug bid for 4 weeks and 200 ug bid for 4 weeks. The primary outcome measure will be the change score on the cognitive subscale of the ADAS at the 8-week visit, comparing the effect of huperzine A 200 micrograms bid to placebo. Secondary analyses will evaluate a wide range of huperzine A dosages, and will examine additional outcome measures. If the results suggest that huperzine A is effective and safe in the treatment of AD, this effort will continue with larger, long-term studies of huperzine A to assess both symptomatic (effect on cognition and clinical status) and disease- modifying effects, and will lead to further efforts to develop advantageous synthetic analogues.